Psychedelic therapy and traditional antidepressants show similar results under open-label conditions

A recent study published in JAMA Psychiatry suggests that psychedelic therapy may not be significantly more effective than standard antidepressants for treating depression when both are compared under similar conditions. The findings provide evidence that the impressive results seen in earlier psychedelic trials might be influenced by study design rather than the unique chemical properties of the drugs themselves. This research helps clarify expectations around new mental health treatments and highlights the importance of fair comparisons in medical science.

Psychedelic therapy combines psychological support with the supervised use of mind-altering substances like psilocybin, which is the active ingredient in “magic” mushrooms. Patients typically undergo preparatory therapy sessions before taking the drug in a controlled clinical environment. They then attend follow-up sessions to help them process the experience.

Scientists conducted this study to address a major methodological problem in psychedelic research known as functional unblinding. In standard clinical trials, neither the patient nor the doctor knows who receives the real drug and who receives an inactive placebo. This blinding process helps prevent a patient’s expectations from influencing the results.

However, functional unblinding occurs when a drug’s physical or psychological effects are so obvious that patients can easily guess whether they received the real treatment. Because psychedelics cause intense changes in perception, practically everyone who takes them in a trial knows they did not receive a placebo. This complete lack of mystery compromises the standard testing procedures used in medical research.

This lack of blinding tends to inflate the perceived benefits of the drug. Patients who realize they received the active psychedelic often experience a boost in hope and positive expectations. At the same time, patients who realize they received the placebo often experience profound disappointment, which can suppress their natural improvement.

“Functional unblinding, i.e. patients realizing who gets placebo and who gets psychedelic in formally blind trials, is the central methodological problem of psychedelic trials. There is agreement in the field that the lack of blinding introduces some bias, but there is no consensus about the magnitude of this bias,” said study author Balázs Szigeti, a postdoctoral clinical data scientist at UCSF’s Translational Psychedelic Research Program.

To solve this problem, the scientists sought to compare treatments on a level playing field by comparing psychedelic therapy to open-label antidepressant trials. This approach allows researchers to measure how both treatments perform when patients are fully aware of their medication.

“Our reasoning is that psychedelic therapy is effectively always open-label (i.e. patients know what treatment they receive), thus, the fair comparison is to other open-label interventions,” Szigeti said.

To conduct the study, the researchers performed a meta-analysis, which is a statistical method that combines data from multiple independent studies to identify broader trends. They searched medical databases for clinical trials treating adults with major depressive disorder. They specifically looked for trials using either open-label standard antidepressants or psychedelic therapies.

The traditional medications included commonly prescribed daily pills, such as escitalopram or fluoxetine. The psychedelic interventions involved mind-altering substances like psilocybin, LSD, or ayahuasca. The final analysis included 24 clinical trials that met their strict criteria.

This dataset consisted of 16 open-label antidepressant trials involving 7,921 patients and 8 psychedelic therapy trials involving 249 patients. The scientists extracted depression severity scores from each study and standardized them using a common metric known as the Hamilton Depression Rating Scale. By converting all the data to a single scale, the researchers could directly compare the symptom improvements reported in both groups.

The researchers used advanced statistical models to estimate the average change in depression symptoms. This change was measured from the beginning of the treatment to the primary endpoint of each trial. The researchers found no meaningful difference in symptom improvement between the two types of treatment.

Both psychedelic therapy and open-label antidepressants led to reductions in depression scores. The statistical models estimated the difference in effectiveness between the two interventions to be a fraction of a point on the depression scale. This negligible difference suggests that psychedelics perform about as well as traditional medications when the playing field is equal.

“When we defined our hypothesis prior to data collection, I wanted to be a psychedelic hero showing that psychedelics are still better than open-label antidepressants, which could have been a strong argument for the superiority of psychedelics,” Szigeti told PsyPost. “While our results are not quite the opposite, we showed no difference rather than antidepressants being better, but was surprised and disappointed once the analysis came together.”

The scientists also examined the impact of blinding on both types of treatment. For standard antidepressants, patients who knew they were taking the drug showed slightly greater improvement than those in blinded trials. This finding provides evidence that simply knowing you are receiving a treatment can boost its effectiveness.

For psychedelic trials, however, the researchers found no difference in outcomes between formally blinded studies and open-label studies. This supports the idea that formal blinding in psychedelic research does not work, as the intense effects of the drugs effectively unblind the patients anyway. Ultimately, the massive advantages previously reported for psychedelics seem partly driven by the poor performance of control groups in blinded trials.

When disappointed placebo patients fail to improve, the active drug looks much better by comparison. The scientists refer to this phenomenon as the “know-cebo” effect, which occurs when patients realize they missed out on the experimental treatment. In some earlier psychedelic trials, patients in the placebo group actually saw their depression worsen due to this disappointment.

While these findings adjust expectations regarding symptom reduction, it is important not to dismiss psychedelic therapy entirely. The researchers point out that their study only measured the reduction of core depressive symptoms. It did not evaluate other potential benefits, such as functional improvements in daily life or differences in side effects.

“Our main finding is that the patient improvement is the same after psychedelic therapy and traditional antidepressants when patients know they are getting an active treatment,” Szigeti explained. “This finding does not mean psychedelics are not effective, only that they are not more effective than traditional antidepressants. These also need to be understood as ‘on average’ effects, some patients are still going to get more benefits from traditional antidepressants, while others from psychedelic therapy.”

Some prior studies suggest that standard medications can cause emotional blunting or sexual dysfunction, while psychedelics might help patients process emotions more deeply. These differing side effect profiles are difficult to compare across widely varied trials. Psychedelics might still offer an alternative option for patients who do not respond well to standard daily medications.

“We received a lot of criticism that we only compared symptom reduction, which is what is measured by classic measures of depression,” Szigeti noted. “It is true that psychedelic therapy may result in better functional outcomes with less side effects. Unfortunately, data on these factors is heterogeneous, making it near impossible to compare across interventions.”

The study also had some limitations regarding the matched data. The psychedelic trials often recruited patients with treatment-resistant depression, which might make their symptoms harder to treat from the start.

Additionally, the measurement timelines differed, with antidepressant trials usually tracking patients for about eight weeks. Psychedelic trials, on the other hand, typically measured outcomes after about three weeks.

Looking ahead, the scientists plan to continue exploring how patients’ expectations shape mental health treatments. “We will have a follow up study comparing patient improvement after blinded antidepressants vs. psychedelic therapy,” Szigeti said. “More broadly, working towards quantitative assessments on the impact of blinding on both treatment and placebo arms for various psychiatric conditions and interventions. My hunch is that the variability is much larger than the field assumes, time will tell.”

The study, “Psychedelic Therapy vs Antidepressants for the Treatment of Depression Under Equal Unblinding Conditions: A Systematic Review and Meta-Analysis,” was authored by Zachary J. Williams, Hannah Barnett, and Balázs Szigeti.